The ability to persist indefinitely in the lungs of healthy individuals indicates that M. tuberculosis has evolved effective mechanisms of defense against the onslaught of the immune response. We have initiated genetic screens to identify mycobacterial “defense factors” by comparing the growth and persistence of transposon-induced mutants in normal mice versus mice with specific immune deficiencies. These studies will elucidate the biology of the host-pathogen interface and could point the way to new strategies to enhance the immune system’s ability to kill persistent mycobacteria.